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PubMed2005

Wnt3a links left-right determination with segmentation and anteroposterior axis elongation.

The alignment of the left-right (LR) body axis relative to the anteroposterior (AP) and dorsoventral (DV) axes is central to the organization of the vertebrate body plan and is controlled by the node/organizer. Somitogenesis plays a key role in embryo morphogenesis as a principal component of AP elongation. How morphogenesis is coupled to axis specification is not well understood. We demonstrate that Wnt3a is required for LR asymmetry. Wnt3a activates the Delta/Notch pathway to regulate perinodal expression of the left determinant Nodal, while simultaneously controlling the segmentation clock and the molecular oscillations of the Wnt/beta-catenin and Notch pathways. We provide evidence that Wnt3a, expressed in the primitive streak and dorsal posterior node, acts as a long-range signaling molecule, directly regulating target gene expression throughout the node and presomitic mesoderm. Wnt3a may also modulate the symmetry-breaking activity of mechanosensory cilia in the node. Thus, Wnt3a links the segmentation clock and AP axis elongation with key left-determining events, suggesting that Wnt3a is an integral component of the trunk organizer.

Animals↗
PubMed1999

1998 Warkany lecture: signaling pathways in development.

Cell-cell signaling pervades all aspects of development, not just in vertebrates, but in all animals (metazoa). It is a typifying characteristic of the major multicellular life forms, animals, plants, and fungi, which diverged about 1.2 billion years ago from a common ancestor descended from a lineage of unicellular life forms. In metazoa, at least 17 kinds of signal transduction pathways operate, each distinguished by its transduction intermediates. Five kinds predominate in early embryonic development, namely, the Wnt, TGF-beta, Hedgehog, RTK, and Notch pathways. Five more are used in late development, and seven more in the functions of differentiated cells. The pathways must have evolved and become conserved in pre-Cambrian times before the divergence of basal members of most of the modern phyla. In metazoan development and physiology, the responses of cells to intercellular signals include cell proliferation, secretion, motility, and transcription. These responses tend to be conserved among metazoa and shared with unicellular eukaryotes and in some cases even with unicellular prokaryotes. Protein components of the responses date back 2 billion years to ancestral eukaryotes or 3 billion to ancestral prokaryotes. Each metazoan developmental process consists of a network of signals and responses, and many of these networks are conserved among metazoa, for example, by insects and mammals. The study of model organisms, even of nonvertebrate groups, is expected to continue to contribute greatly to the understanding of mammalian development and to offer opportunities to analyze the effects of toxicants on development, as well as opportunities to devise incisive assays for toxicants.

Animals↗
PubMed1999

The Notch/Jagged pathway inhibits proliferation of human hematopoietic progenitors in vitro.

The cell surface receptor Notch1 is expressed on CD34+ hematopoietic precursors, whereas one of its ligands, Jagged1, is expressed on bone marrow stromal cells. To examine the role of Notch signaling in early hematopoiesis, human CD34+ cells were cultured in the presence or absence of exogenous cytokines on feeder layers that either did or did not express Jagged1. In the absence of recombinant growth factors, Jagged1 decreased myeloid colony formation by CD34+ cells, as well as 3H-thymidine incorporation and entry into S phase. In the presence of a strong cytokine signal to proliferate and mature, (interleukin 3 [IL-3] and IL-6, stem cell factor [SCF], and G-CSF), Jagged1 did not significantly alter either the fold expansion or the types of colonies formed by CD34+ cells. However, in the presence of SCF alone, Jagged1 increased erythroid colony formation twofold. These results demonstrate that Notch can modulate a growth factor signal, and that in the absence of growth factor stimulation, the Jagged1-Notch pathway preserves CD34+ cells in an immature state.

3T3 Cells↗
PubMed2005

Notch signaling in hematopoietic stem cells.

The molecular basis of the hematopoietic stem cell (HSC) "niche" has gradually been elucidated. This new knowledge may help us understand how the self-renewal of HSCs is physiologically regulated and may give us clues for developing methods for ex vivo HSC expansion. The Notch pathway is an environmental signaling system that may play an important role in the HSC niche. In this review, we focus on the role of Notch signaling in the regulation of hematopoietic stem and progenitor cells in both embryo and adult hematopoiesis and clarify what is known regarding the self-renewal of HSCs.

Animals↗
PubMed2002

A Delta-Notch signaling border regulated by Engrailed/Invected repression specifies boundary cells in the Drosophila hindgut.

The Drosophila hindgut develops three morphologically distinct regions along its anteroposterior axis: small intestine, large intestine and rectum. Single-cell rings of 'boundary cells' delimit the large intestine from the small intestine at the anterior, and the rectum at the posterior. The large intestine also forms distinct dorsal and ventral regions; these are separated by two single-cell rows of boundary cells. Boundary cells are distinguished by their elongated morphology, high level of both apical and cytoplasmic Crb protein, and gene expression program. During embryogenesis, the boundary cell rows arise at the juxtaposition of a domain of Engrailed (En)- plus Invected (Inv)-expressing cells with a domain of Delta (Dl)-expressing cells. Analysis of loss-of-function and ectopic expression phenotypes shows that the domain of Dl-expressing cells is defined by En/Inv repression. Further, Notch pathway signaling, specifically the juxtaposition of Dl-expressing and Dl-non-expressing cells, is required to specify the rows of boundary cells. This Notch-induced cell specification is distinguished by the fact that it does not appear to utilize the ligand Serrate and the modulator Fringe.

Animals↗
PubMed2005

Influence of Notch on dorsoventral compartmentalization and actin organization in the Drosophila wing.

Compartment boundaries play key roles in tissue organization by separating cell populations. Activation of the Notch receptor is required for dorsoventral (DV) compartmentalization of the Drosophila wing, but the nature of its requirement has been controversial. Here, we provide additional evidence that a stripe of Notch activation is sufficient to establish a sharp separation between cell populations, irrespective of their dorsal or ventral identities. We further find that cells at the DV compartment boundary are characterized by a distinct shape, a smooth interface, and an accumulation of F-actin at the adherens junction. Genetic manipulation establishes that a stripe of Notch activation is both necessary and sufficient for this DV boundary cell phenotype, and supports the existence of a non-transcriptional branch of the Notch pathway that influences F-actin. Finally, we identify a distinct requirement for a regulator of actin polymerization, capulet, in DV compartmentalization. These observations imply that Notch effects compartmentalization through a novel mechanism, which we refer to as a fence, that does not depend on the establishment of compartment-specific cell affinities, but does depend on the organization of the actin cytoskeleton.

Actins↗
PubMed1999

Overexpression of the m4 and malpha genes of the E(spl)-complex antagonizes notch mediated lateral inhibition.

Intercellular signalling mediated by Notch proteins is crucial to many cell fate decisions in metazoans. Its profound effects on cell fate and proliferation require that a complex set of responses involving positive and negative signal transducers be orchestrated around each instance of signalling. In Drosophila the basic-helix-loop-helix (bHLH) repressor encoding genes of the E(spl) locus are induced by Notch signalling and mediate some of its effects, such as suppression of neural fate. Here we report on a novel family of Notch responsive genes, whose products appear to act as antagonists of the Notch signal in the process of adult sensory organ precursor singularization. They, too, reside in the E(spl) locus and comprise transcription units E(spl) m4 and E(spl) malpha. Overexpression of these genes causes downregulation of E(spl) bHLH expression accompanied by cell autonomous overcommitment of sensory organ precursors and tufting of bristles. Interestingly, negative regulation of the Notch pathway by overexpression of E(spl) m4 and malpha is specific to the process of sensory organ precursor singularization and does not impinge on other instances of Notch signalling.

Amino Acid Sequence↗
PubMed2003

Notch signaling controls multiple steps of pancreatic differentiation.

Multiple cell types of the pancreas appear asynchronously during embryogenesis, which requires that pancreatic progenitor cell potential changes over time. Loss-of-function studies have shown that Notch signaling modulates the differentiation of these progenitors, but it remains unclear how and when the Notch pathway acts. We established a modular transgenic system to heritably activate mouse Notch1 in multiple types of progenitors and differentiated cells. We find that misexpression of activated Notch in Pdx1-expressing progenitor cells prevents differentiation of both exocrine and endocrine lineages. Progenitors remain trapped in an undifferentiated state even if Notch activation occurs long after the pancreas has been specified. Furthermore, endocrine differentiation is associated with escape from this activity, because Ngn3-expressing endocrine precursors are susceptible to Notch inhibition, whereas fully differentiated endocrine cells are resistant.

Animals↗
PubMed2005

Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation.

Notch pathway is crucial for stem/progenitor cell maintenance, growth and differentiation in a variety of tissues. Using a transgenic cell ablation approach, we found in our previous study that cells expressing Notch1 are crucial for prostate early development and re-growth. Here, we further define the role of Notch signaling in regulating prostatic epithelial cell growth and differentiation using biochemical and genetic approaches in ex vivo or in vivo systems. Treatment of developing prostate grown in culture with inhibitors of gamma-secretase/presenilin, which is required for Notch cleavage and activation, caused a robust increase in proliferation of epithelial cells co-expressing cytokeratin 8 and 14, lack of luminal/basal layer segregation and dramatically reduced branching morphogenesis. Using conditional Notch1 gene deletion mouse models, we found that inactivation of Notch1 signaling resulted in profound prostatic alterations, including increased tufting, bridging and enhanced epithelial proliferation. Cells within these lesions co-expressed both luminal and basal cell markers, a feature of prostatic epithelial cells in predifferentiation developmental stages. Microarray analysis revealed that the gene expression in a number of genetic networks was altered following Notch1 gene deletion in prostate. Furthermore, expression of Notch1 and its effector Hey-1 gene in human prostate adenocarcinomas were found significantly down-regulated compared to normal control tissues. Taken together, these data suggest that Notch signaling is critical for normal cell proliferation and differentiation in the prostate, and deregulation of this pathway may facilitate prostatic tumorigenesis.

Amyloid Precursor Protein Secretases↗
PubMed2005

Inhibition of Notch signaling enhances tissue repair in an animal model of multiple sclerosis.

Oligodendrocytes (OLs) fail to regenerate myelin destroyed by the immune attack in multiple sclerosis (MS) and lesion areas are eventually largely occupied by astrocytic scar tissue. Loss of OLs in MS does not account for the limited myelin repair as lesions contain a considerable number of OL precursor cells (OPC). Activation of the Notch pathway has been shown to provide inhibitory signals for OPC and to hamper their ability to produce myelin during CNS development. Here we show that gamma-secretase inhibition of Notch signaling within OL of CNS of SJL/J mice with experimental autoimmune encephalomyelitis (EAE) significantly enhanced clinical recovery and in the CNS, promoted remyelination and reduced axonal damage. Functional assays confirmed decreased Notch signaling in inhibitor-treated groups. Therefore, gamma-secretase inhibition led to an environment more conducive to myelin repair and axonal survival. Our results suggest that manipulation of the environment associated with Notch activation in the mature CNS provides a promising therapeutic target in MS.

Amyloid Precursor Protein Secretases↗
PubMed2003

Periodic notch inhibition by lunatic fringe underlies the chick segmentation clock.

The segmented aspect of the vertebrate body plan first arises through the sequential formation of somites. The periodicity of somitogenesis is thought to be regulated by a molecular oscillator, the segmentation clock, which functions in presomitic mesoderm cells. This oscillator controls the periodic expression of 'cyclic genes', which are all related to the Notch pathway. The mechanism underlying this oscillator is not understood. Here we show that the protein product of the cyclic gene lunatic fringe (Lfng), which encodes a glycosyltransferase that can modify Notch activity, oscillates in the chick presomitic mesoderm. Overexpressing Lfng in the paraxial mesoderm abolishes the expression of cyclic genes including endogenous Lfng and leads to defects in segmentation. This effect on cyclic genes phenocopies inhibition of Notch signalling in the presomitic mesoderm. We therefore propose that Lfng establishes a negative feedback loop that implements periodic inhibition of Notch, which in turn controls the rhythmic expression of cyclic genes in the chick presomitic mesoderm. This feedback loop provides a molecular basis for the oscillator underlying the avian segmentation clock.

Animals↗
PubMed2005

The role of notch in modeling and maintaining the vasculature.

The Notch proteins encompass a family of transmembrane receptors that have been highly conserved through evolution as mediators of cell fate, and are comprised of 4 members in mammals (Notch1 to Notch4). Following intra cellular processing of the full-length protein, Notch is expressed at the cell surface as a heterodimeric receptor. Engagement by ligand results in a 2-step cleavage of the Notch heterodimer, releasing the intracellular domain of Notch and allowing translocation to the nucleus. The intracellular domain of Notch interacts with the DNA-binding factor, CSL, resulting in transactivation at various promoters, in particular those of various basic helix-loop-helix factors of the HES (Hairy and Enhancer of Split) and HRT families (Hairy-Related Transcription factor). Recent findings implicate Notch as playing a critical and non-redundant role in vascular development and maintenance. This article briefly reviews vessel development and Notch signaling and highlights studies that examine Notch functions such as proliferation, cell survival, migration, adhesion, and mesenchymal transformation in the vasculature. Human diseases caused by Notch pathway members are also discussed.

Animals↗
PubMed2004

Notch ligands Delta 1 and Jagged1 transmit distinct signals to T-cell precursors.

Signaling through the Notch pathway plays an essential role in inducing T-lineage commitment and promoting the maturation of immature thymocytes. Using an in vitro culture system, we show that 2 different classes of Notch ligands, Jagged1 or Delta1, transmit distinct signals to T-cell progenitors. OP9 stromal cells expressing either Jagged1 or Delta1 inhibit the differentiation of DN1 thymocytes into the B-cell lineage, but only the Delta1-expressing stromal cells promote the proliferation and maturation of T-cell progenitors through the early double-negative (DN) stages of thymocyte development. Whereas the majority of bone marrow-derived stem cells do not respond to Jagged1 signals, T-cell progenitors respond to Jagged1 signals during a brief window of their development between the DN1 and DN3 stages of thymic development. During these stages, Jagged1 signals can influence the differentiation of immature thymocytes along the natural killer (NK) and gamma delta T-cell lineages.

Animals↗
PubMed2005

Notch signaling in the mammalian central nervous system: insights from mouse mutants.

The Notch pathway, although originally identified in fruit flies, is now among the most heavily studied in mammalian biology. In mice, loss-of-function and gain-of-function work has demonstrated that Notch signaling is essential both during development and in the adult in a multitude of tissues. Prominent among these is the CNS, where Notch has been implicated in processes ranging from neural stem cell regulation to learning and memory. Here we review the role of Notch in the mammalian CNS by focusing specifically on mutations generated in mice. These mutations have provided critical insight into Notch function in the CNS and have led to the identification of promising new directions that are likely to generate important discoveries in the future.

Animals↗
PubMed2025

Genetic insight into lung neuroendocrine tumors: Notch and Wnt signaling pathways as potential targets.

BACKGROUND: The molecular landscape of lung neuroendocrine neoplasms is still poorly characterized, making it difficult to develop a molecular classification and personalized therapeutic approaches. Significant clinical heterogeneity of these malignancies has been highlighted among poorly differentiated histotypes and within the subgroup of well-differentiated neuroendocrine tumors (NET). Currently, the main prognostic factors of lung NET include stage, histotype, grade, peripheral location, and demographic parameters. To gain deeper insights into the genomic underpinnings of lung NETs, we conducted a pilot investigation to uncover potential genetic mutations and copy number variations (CNVs) implicated in their pathogenesis. METHODS: Formalin-fixed, paraffin-embedded intraoperative tumor biopsies and matched peripheral blood mononuclear cell samples were collected from six consecutive patients with lung NETs. The whole exome sequencing (WES) was performed to profile germline and somatic mutations, identify novel genetic alterations, and detect CNVs. Clinical and pathological data were systematically documented at diagnosis and during follow-up. RESULTS: The WES analysis identified a subset of mutations shared between germline and somatic; some were of particular clinical interest as they were associated with tumor proliferation and potential therapeutic targets such as the genes KDM5C, ATR, COL7A1, NOTCH4, PTPRS, SMO, SPEN, SPTA1, TAF1. These mutations were predominantly linked to chromatin remodeling and were involved in critical oncogenic pathways such as Notch and Wnt signaling. CONCLUSIONS: This pilot study highlights the potential role of NGS analysis on solid biopsy in the assessment of the mutational profile of lung NET. A comparison of germline and somatic mutations is critical to identifying putative tumor driver mutations. In perspective, the enrichment of a subpopulation of cancer cells in the blood, with one or more specific mutations, is information of enormous clinical relevance, either for prognosis or therapeutic decisions. Translational studies on large prospective series are required to establish the role of liquid biopsy in lung NET.

Humans↗
PubMed2001

Delta signaling from the germ line controls the proliferation and differentiation of the somatic follicle cells during Drosophila oogenesis.

The body axes of Drosophila are established during oogenesis through reciprocal interactions between the germ line cells and the somatic follicle cells that surround them. The Notch pathway is required at two stages in this process: first, for the migration of the follicle cells around the germ line cyst and, later, for the polarization of the anterior-posterior (A-P) axis of the oocyte. Its function in these events, however, has remained controversial. Using clonal analysis, we show that Notch signaling controls cell proliferation and differentiation in the whole follicular epithelium. Notch mutant follicle cells remain in a precursor state and fail to switch from the mitotic cell cycle to the endocycle. Furthermore, removal of Delta from the germ line produces an identical phenotype, showing that Delta signals from the germ cells to control the timing of follicle cell differentiation. This explains the axis formation defects in Notch mutants, which arise because undifferentiated posterior follicle cells cannot signal to polarize the oocyte. Delta also signals from the germ line to Notch in the soma earlier in oogenesis to control the differentiation of the polar and stalk follicle cells. The germ line therefore regulates the development of the follicle cells through two complementary signaling pathways: Gurken signals twice to control spatial patterning, whereas Delta signals twice to exert temporal control.

Animals↗
PubMed2003

Notch signaling in vascular development.

Notch signaling is an extremely conserved and widely used mechanism regulating cell fate in metazoans. Interaction of Notch receptors (Notch) with their ligands (Delta-like or Jagged) leads to cleavage of the Notch intracellular domain (NICD) that migrates into the nucleus. In the nucleus, NICD associates with a transcription factor, RBP-Jk. The NICD-RBP-Jk complex, in turn, upregulates expression of primary target genes of Notch signaling, such as hairy and enhancer of split (HES) and HES-related repressor protein (HERP) transcriptional repressors. Recent evidence has demonstrated that the Notch pathway is involved in multiple aspects of vascular development, including proliferation, migration, smooth muscle differentiation, angiogenic processes, and arterial-venous differentiation. In this brief review, we focus on ligands, receptors, and target genes of Notch signaling in the vascular system and discuss (1) tissue distribution; (2) gain- and loss-of-function studies; and (3) the role of Notch components in human diseases involving the vascular system.

Alagille Syndrome↗
PubMed2006

Structures of CSL, Notch and Mastermind proteins: piecing together an active transcription complex.

Notch signaling mediates communication between cells, and is essential for proper cell fate decisions in the developing embryo and the adult organism. Signaling initiates proteolytic release of the receptor Notch from the membrane, whereupon the intracellular portion of Notch (NotchIC) localizes to the nucleus and engages the DNA-binding transcription factor CSL. CSL is required for both repression and activation of Notch target genes, and is the focal point of a transcriptional switch, mediating interactions with transcriptional coregulators. Activation of transcription requires corepressor displacement from CSL by NotchIC and the recruitment of the transcriptional coactivator Mastermind to the complex. Several recently determined and exciting structures of CSL, NotchIC, and an active transcription complex composed of CSL, NotchIC and Mastermind have revealed new insights into transcriptional regulation in the Notch pathway.

Animals↗